Urinary cyclic AMP in man is derived in roughly equal amounts from two sources: plasma (by glomerular filtration) and the kidney ("nephrogenous" cyclic AMP). A variety of hormones influence plasma levels of the nucleotide, whereas the major (if not sole) determinant of nephrogenous cyclic AMP is the circulating titer of parathyroid hormone (PTH). Our objective has been to demonstrate that nephrogenous cyclic AMP is a valid index of parathyroid function. These investigations are particularly timely because of the recent recognition of the many problems inherent in measuring PTH. In our studies, nephrogenous cyclic AMP is quantitated by the simultaneous measurement of endogenous creatinine and cyclic AMP clearances. Immunoreactive PTH is also measured for direct comparison. The clearance ratio of cyclic AMP is the simplest expression of nephrogenous cyclic AMP, values progressively greater than unity indicating increasing renal contributions of the nucleotide. We have accumulated data on 10 chronically hypoparathyroid patients, 35 normal subjects and 39 hyperparathyroid patients. The clearance ratios (plus or minus SEM) in the three groups, respectively, are: 1.23 plus or minus 0.03, 1.81 plus or minus 0.12 and 3.64 plus or minus 0.13. The analysis is also valid in mild hyperparathyroidism and in azotemic hyperparathyroid patients. Parathyroid hormone assays were in the normal range in about 20% of hyperparathyroid patients. Retrospective analysis has revealed that correlation of cyclic AMP excretion with simultaneously determined creatinine clearance provides an extraordinarily simple test, which will be of wide availability and utility. Recent preliminary data indicates that nephrogenous cyclic AMP is also an excellent index of parathyroid function within "normal" physiologic limits. The measurement may also be very useful in the study of patients with subtle lesions of calcium metabolism (e.g., idiopathic hypercalciuria).